C. Key issues raised by interested parties and the Pharmacy and Therapeutics Committee pertaining to the clinical review of the following therapeutic classes:

Public comments:

Growth Hormone:

The Committee was asked to consider information regarding clinical trial results including indications, safety, dosing, storage, type of preservative, long term efficacy, as well as the different drug delivery devices available, patient support programs including multi-lingual programs, patient education, and reducing drug waste.

Erythropoiesis Stimulating Agents (ESA):

The Committee was asked to consider information regarding clinical trial results including indications, efficacy, safety, the recent Food and Drug Administration (FDA) updates, dosing frequency, as well as the impact of kidney disease, renal dialysis, anemia, and treatment with ESAs on an individual.

Ophthalmic Non-Steroidal Anti-Inflammatory Drugs (NSAID):

The Committee was asked to consider information regarding clinical trial results for nepafenac including indications, drug metabolism and corneal penetration.

Pharmacy and Therapeutics Committee Comments:

The Committee discussed the growth hormone patient support programs, and asked for clarification regarding the availability of these programs from the various manufacturers, as well as the
variability in language translation services offered by the programs. A question was raised regarding data on experience with drug waste and the presenter indicated little literature was available in this area. Questions were also raised by the Committee regarding the use of growth hormone in neonates and the use of benzyl alcohol as a preservative. The presenter indicated that neonatal growth hormone therapy would potentially occur on an outpatient basis, and there are growth hormone products without benzyl alcohol that would be available for use in this population.

A committee member asked for clarification of the indications for the drugs in the ESA therapeutic category, and the presenter compared the indications of epoetin alfa and darbepoetin alfa,
confirming that while both Epogen and Procrit are epoetin alfa, they are marketed differently by the manufacturer.

Dr. Rogler began with a review of the drugs in the therapeutic class and noted that all the drugs are the same chemical entity marketed under multiple brand names. She provided a description of the
deficiencies and syndromes (adult and pediatric) that are treated with somatropin, a recombinant DNA-derived growth hormone. She noted the adverse events that can occur during therapy. She indicated the
majority of products have multiple dosing systems, each of the product manufacturers offers patient support services, and a range of preservatives are available. She concluded by mentioning the Update of
Guidelines for the Use of Growth Hormone in Children: The Lawson Wilkins Pediatric Endocrinology Society Drug and Therapeutic Committee which notes no observable differences between products at
approved doses, and no evidence of a difference in outcomes with the different injection systems.

Dr. Correia provided the Department's clinical review for this category. He noted there is no comparative evidence between the products in this class because they are all the same drug, and they produce
identical clinical effects. He indicated different manufacturers have pursued different indications, package sizes and delivery devices for their particular brand name product. He discussed the use of benzyl
alcohol as a preservative, noting it must be considered in the context that it is a minute quantity of preservative that is actually present in an infant dose of growth hormone. He also indicated three of the
seven brand name products under review which might be used in neonates are available without benzyl alcohol. He mentioned there is no FDA-approved indication for any of these agents in infants (see note below)*, but acknowledged utilization of these products in neonates, noting use in neonates should be minor in the Medicaid pharmacy program. He reiterated the endocrine society statements indicating no observable differences in the results obtained from the different preparations or various injection systems as long as the appropriate regimen is followed. He also noted all of the manufacturers have patient support programs, and those that provide unique delivery devices to patients do so at no additional charge. He concluded by reiterating there is no comparative clinical issue as the drugs in the review are all the same drug. He also stated that issues pertaining to a specific or rare FDA-approved indication for a particular brand could be addressed in prior authorization criteria if needed, and that it would be preferable to include as broad a selection of these products as possible.

A Committee member inquired if the "Update of Guidelines for the Use of Growth Hormone in Children: The Lawson Wilkins Pediatric Endocrinology Society Drug and Therapeutic Committee" was an evidence based document. Dr Rogler indicated that it was, and it was published in a peer-reviewed journal. Another member commented that it appeared the support programs and delivery systems were what actually differentiated the products and inquired if there was anything in the literature comparing those. Dr. Correia referred to Dr. Rogler's presentation regarding the Update of Guidelines for the Use of Growth Hormone in Children which indicates there is no evidence that clinical outcomes differ among different devices.

* Please note: Dr. Correia intended to convey that the FDA labeling does not indicate a use in neonates (not infants as incorrectly stated during the meeting), and in fact there is no clinical evidence from studies in the FDA labeling for any of the somatropins inclusive of patients younger than two years of age.

Dr. Rogler described the agents in the review, noting that Epogen and Procrit are identical products (recombinant human epoetin alfa), Aranesp (darbepoetin alfa) is similar to epoetin alfa, and all three
products have the same biological effects as endogenous erythropoietin. She presented the indications for the agents, and provided background information regarding hemoglobin (Hb), hematocrit (HCT), and
erythropoietin. She discussed the FDA alerts for the agents in this class, including the most recent alert from November 8, 2007. She shared several of the current theories about the causes of the adverse
events described in the boxed warnings.

She spoke about the correction of anemia associated with chronic kidney disease (CKD), providing background on CKD, the boxed warning with regard to renal failure, clinical trials in the product inserts of
the ESAs, indications, contraindications, warnings, and dosing regimens, including pediatric dosing. She described a comparative trial between Epogen/Procrit versus Aranesp, and mentioned the three updated
statements with regard to hemoglobin in the National Kidney Foundation (NKF) Kidney Disease Outcomes Quality Initiative (K/DOQI) new Anemia Guidelines.

She then spoke about the correction of anemia in cancer patients on chemotherapy. She provided background information on anemia in cancer, and background on dosing, efficacy, and safety of the ESAs
for this indication. She discussed the results of the Agency for Healthcare Research and Quality (AHRQ) systematic review of the comparative effectiveness of epoetin alfa and darbepoetin for the management
of anemia associated with cancer treatment. She discussed the American Society of Clinical Oncology/American Society of Hematology (ASCO/ASH) Guidelines published December 1, 2007 which indicate the ASCO/ASH Update Committee considers ESAs to be equivalent with respect to effectiveness and safety.

Lastly, she discussed additional indications for Epogen and Procrit, including the treatment of anemic patients scheduled to undergo certain types of surgeries, and the treatment of anemia associated with
zidovudine-treated HIV-infected patients. She concluded, noting all three agents have the same FDA boxed warning, that research is ongoing in this area, and to date, no clinical trial has demonstrated
clinical superiority among the agents in the review.

Dr. Correia provided the Department's clinical review for this category. He noted there are actually only two drugs in the category, epoetin (marketed under two different trade names) and darbepoetin, and
epoetin has two indications that are not available for darbepoetin. He noted clinical information had been submitted for review identifying certain off-label uses for the ESAs, and clarified that although many of the uses submitted are listed, they are not actually supported by the compendia, and some of those off-label uses are contrary to the most recently issued FDA warnings for these drugs. He indicated both epoetin
and darbepoetin have multiple dosing regimens, and based on concomitant treatment issues (such as frequency of dialysis), the differences in the dosing regimens may not always be significant in practice.

He indicated that the continued evolution of knowledge about this class of drugs is demonstrated by recent increased cautions for use dependent upon concomitant disease states and dosing, and continued
postmarketing surveillance may further reveal relative risks or benefits to be variable dependent upon concomitant diseases, particularly those which may be adversely impacted by cell growth stimulation or
thromboembolic complications. He also noted a possible correlation may be found for comorbidity and adverse effect related to extended exposure to ESAs dosed less frequently as opposed to shorter,
intermittent exposure to agents dosed more frequently.

He discussed the updated 2007 clinical practice guidelines from ASCO/ASH which identify epoetin and darbepoetin to be equivalent with respect to efficacy and safety. He also discussed the AHRQ report on
the comparative effectiveness and safety of these agents which found no difference between epoetin and darbepoetin for hemoglobin response, reduced need for blood transfusions, risk of thromboembolic
events, and quality of life measurements, although the clinical significance of the quality of life studies remains uncertain due to inconsistent results. In conclusion, Dr. Correia noted the epoetin products are
identical, and although either epoetin or darbepoetin may have advantages or be preferable in specific situations or at different stages of disease progression, neither demonstrates an overall advantage.

Dr. Rogler provided background information on cachexia and megestrol acetate, noting that the megestrol acetate tablets are excluded from the review because they are not indicated for cachexia. She
discussed two clinical trials assessing clinical efficacy of megestrol acetate oral suspension which concluded patients in the megestrol group had a significantly greater change in their weight and appetite when
compared to placebo. She discussed dosing and administration, and precautions for the agents in the review as well as use in special populations including pregnancy, HIV infected women, and pediatric and
geriatric patients. In conclusion, she stated megestrol acetate oral suspension at a dose of 800 mg/20 ml is equivalent to 625 mg/5 ml of Megace ES, and in clinical trials, daily doses of 400 and 800 mg/day of
megestrol acetate oral suspension as either 800 mg/20 ml or 625mg/5 ml were found to be clinically effective.

Dr. Correia provided the Department's clinical review for this category. He reiterated the products in the review are the same drug in different dosage preparations. They are dosed once a day, as either a 5ml dose or a 20ml dose depending on the product selection. In clinical trials they were both found to be clinically effective at equivalent doses. He concluded there is no evidence of clinical superiority between
the products.

4. Proposal to identify preferred drugs in the therapeutic class of Carbamazepine Derivatives

Dr. Rogler introduced the drugs included in the review. She provided a description of the different types of seizures, trigeminal neuralgia, and bipolar 1 disorder. She described the adult and pediatric
indications, metabolism, drug interaction potential, warnings, and precautions for both oxcarbazepine and carbamazepine. She spoke about the use of these drugs in special populations including pregnancy,
pediatrics, the elderly and in patients with renal failure. She also spoke about the boxed warnings and contraindications for carbamazepine. In summary, Dr. Rogler noted she found no comparative data
between the drugs in the review, and concluded carbamazepine derivatives have similar profiles.

Dr. Correia provided the Department's clinical review for this category. He noted there are only two actual drugs in the category, carbamazepine and oxcarbazepine, which are available in a variety of dosage forms. He noted carbamazepine has the broader range of indications of the two, and oxcarbazepine, which is chemically related to carbamazepine, was developed with hope of matching or improving
response and/or decreasing adverse effects (Stevens-Johnson Syndrome, Toxic Epidermal Necrolysis) in comparison to carbamazepine. He pointed out, however, that both drugs have the potential to cause
Stevens-Johnson Syndrome, Toxic Epidermal Necrolysis and hyponatremia. He indicated the two drugs have slight differences in the way they are metabolized and slightly different drug interaction profiles.

He found no head to head trials of carbamazepine and oxcarbazepine, although he described one comparison of high versus low dose oxcarbazepine in patients inadequately controlled on and transitioned
from carbamazepine that found those patients taking the high dose of oxcarbazepine took longer to reach one of four measures of seizure exacerbation versus the low dose. He noted in this comparison, the carbamazepine dose was not maximized.

He mentioned an FDA alert issued yesterday (12/12/2007) addressing the dangerous and potentially fatal skin reactions Stevens Johnson Syndrome and Toxic Epidermal Necrolysis that can be caused by
carbamazepine therapy. The alert stated these reactions are significantly more common in patients with a particular genetic marker which occurs almost exclusively in broad areas of Asia, including South Asian
Indians, and recommends that patients with this ancestry be tested for the genetic marker before carbamazepine therapy is started in order to adequately assess the risks versus benefits of therapy. He
noted the alert is unclear whether this warning may also apply to these skin reactions caused by other drugs which have this adverse effect, including oxcarbazepine (susceptibility to the disease versus
sensitivity to the drug). He concluded there is no comparative evidence to indicate any one of these products is better overall.

The Committee members discussed the off-label use of oxcarbazepine for anger management, road rage, and domestic violence, and noted the manufacturer of the brand product was applying for additional FDA indications. The Committee also discussed anecdotal evidence regarding an increase in seizure activity when changing from one brand of these medications to another with generic substitution, and it
was noted that with narrow therapeutic index drugs, it becomes an issue of drugs being bioequivalent versus therapeutically equivalent. It was noted that there may be cause for concern, but it is difficult to
quantify the scope of the problem. It was also noted that oxcarbazepine is often added to pediatric anti-seizure medication regimens because as children grow, they may develop partial seizures. Dr. Martin
mentioned at this time that all medications in the Preferred Drug Program remain available, those that are non-preferred are available with prior authorization, and the prescriber's decision prevails.

Dr. Rogler introduced the medications in the class, and mentioned one of the products is a suspension, versus the others which are solutions. She noted the products are primarily indicated for short term use for the reduction of ocular pain and inflammation following corneal surgery, and pointed out one product has an additional indication for temporary relief of ocular itching caused by seasonal allergic
conjunctivitis. She provided background on ocular inflammation, and noted all the products in the category have the same mechanism of action. She discussed contraindications, warnings and precautions for drugs in this category, and use in special populations, including pediatrics, pregnancy, and in patients with certain ocular and non-ocular co-morbidities. She then discussed three head to head clinical trials, and
in conclusion noted that all ophthalmic NSAIDs reduce inflammation and also provide pain control.

Dr. Correia provided the Department's clinical review for this category. He discussed the indications for the drugs, and noted the dosing for the drugs in the category varies from two times a day to four times a day. He mentioned bromfenac, which is dosed twice a day, contains a sulfite preservative which may be a problem for patients with a sulfite allergy. He indicated clinical assessments of pharmacokinetics such as drug penetration and predicted efficacy based on surrogate chemical markers were frequently derived from animal studies based on small animals or animal eyes with physical proportions dramatically
different from human eyes. He noted, in his opinion, that findings from these animal and laboratory models are useful scientifically, but should not be the basis for human clinical practice decisions, and
speculation that a drug will have an equivalent human effect based on laboratory or animal findings is of marginal relevance compared to actual therapeutic outcomes in human trials.

He noted nepafenac has been described as having a therapeutic advantage which is attributed to increased ocular penetration or lipophilicity, when human clinical data, including head to head trials with
clinical outcomes indicate this may not be an advantage in all circumstances, and might represent a relative risk versus benefit situation. He discussed several clinical trials, one non-comparative placebo
controlled trial, one comparative trial that was halted early due to patient safety concerns pertaining to corneal haze and slower healing with the drug identified as more lipophilic, and one indicating after only a
seven day assessment period, no statistical difference in average time to healing over the seven days. He further noted that the drugs in this category are indicated for short term use, and extended use
beyond fourteen days may increase risk of corneal injury or damage, especially in patients with certain comorbidities, including but not limited to diabetes and rheumatoid arthritis. In conclusion, he stated the
available clinical evidence currently suggests that different drugs may offer potential advantages or risks depending upon co-morbidity or specific surgical procedures involved, and a review of the clinical
evidence available, including very limited comparative evidence, did not reveal any overall clinical superiority for any drug in this class.

A Committee member inquired whether patients with diabetes or rheumatoid arthritis were included in any of the clinical trials, and if so, how they did. Dr. Correia responded that most trials excluded patients with these comorbidities and with any previous ophthalmic issues to eliminate confounding factors when trying to document the effect of the drug.

Dr. Rogler introduced the medications in the class including the different preservatives in the products. She provided background on glaucoma including childhood glaucoma, risk factors for glaucoma, and eye drops commonly used to treat the disease. She spoke about brimonidine including indications, dosing, pharmacology, contraindications, warnings and precautions, use in special populations (pregnancy,
pediatrics, elderly), and monitoring. She discussed a clinical trial comparing two strengths of brimonidine-Purite and one strength of brimonidine which showed very similar adverse event data, and effectiveness
in lowering intraocular pressure (IOP) in patients with glaucoma and ocular hypertension for all three products, with equal efficacy between the two Purite products. She concluded the brimonidine products
(0.15% and 0.2%) are effective in reducing IOP for the long-term management of glaucoma or ocular hypertension. She also mentioned in conclusion that the apraclonidine 0.5% product is only indicated for
short-term adjunctive therapy in patients on maximally tolerated therapy with other agents who require additional IOP reduction.

Dr. Correia provided the Department's clinical review for this category. He described the drugs in the review including their indications, strengths, and preservatives. He noted apraclonidine 1% is only used
to decrease IOP during surgery, and apraclonidine 0.5% is indicated for short term use as adjunct therapy when additional IOP reduction is necessary, and is often used when it is necessary to delay surgery,
although tolerance tends to develop rapidly with this drug. He indicated comparative clinical studies between the brimonidine products should be interpreted cautiously, as there are enough significant
differences in dosing and duration between studies to be responsible for conflicting results. He noted FDA approved dosing for these products is three times a day, but reviewed literature indicates that they
are sometimes dosed twice a day in clinical practice, and the comparative clinical trials utilize both of these regimens. He noted some studies showed equivalent pressure lowering with the twice a day
dosing, while others demonstrated greater efficacy with the three times a day dosing, and currently, three times a day dosing is considered the preferable regimen to assure therapeutic effect.

He spoke about the twelve-month study cited as demonstrating a large difference in tolerability between products with benzalkonium chloride or sodium perborate as the preservative. After review of the
complete original published studies to clarify the actual clinical relevance of these claims, Dr. Correia indicated the original article identifies a 41percent relative decrease in allergic conjunctivitis, when the
actual difference in conjunctivitis was only 6 1/2 percent. The researchers attributed this difference not to type of preservative, but rather to concentration of brimonidine used. He also noted tolerance does seem to develop to use of brimonidine, although not as dramatically or uniformly as it does to apraclonidine. He concluded there is no evidence of overall superiority for any one product reviewed, and brimonidine and apraclonidine have different places in therapy, with apraclonidine having application to a more limited patient population.

E. Executive Session:

The Committee recessed the public session at 11:50 A.M. to go into executive session for review of financial information relating to the determination of preferred drugs in the following classes: Growth
Hormone, Erythropoiesis Stimulating Agents, Progestins (for Cachexia), Carbamazepine Derivatives, Ophthalmic Non-Steroidal Anti-Inflammatory Drugs, Alpha-2 Adrenergic Agonists (for Glaucoma). No
official action was taken in the executive session. The executive session was recessed at 1:40 P.M.

F. Recommendations of the Pharmacy and Therapeutics Committee:

The following recommendations developed by the P&T Committee are to be submitted to the Commissioner of Health for final determination.

Description of Recommendations

Commissioner's Final Decision

Proposal: Identification of preferred drugs in the category of Growth Hormones

A. Based on the submitted or presented clinical information and on the financial
information provided during the executive session, the Committee unanimously recommended the following:

Q: Are you using the non-preferred product for an FDA approved indication that is not listed for a preferred agent?

Dr. Martin (Chairperson) noted the recommendations made in this category were made with the additional consideration of product storage, type of preservative, dosing devices, and FDA indications, and it is the opinion of the Committee that a wide range of products are being recommended as preferred products.

Approved as Recommended

Proposal: Identification of preferred drugs in the category of Erythropoiesis Stimulating Agents (ESAs)

A. Based on the submitted or presented clinical information and on the financial information provided during the executive session, the Committee recommended the following with a vote of 6 to 1:

Preferred DrugsAranesp (darbepoetin alfa), Epogen (epoetin alfa)

Non-preferred DrugsProcrit (epoetin alfa)

B. The Committee unanimously recommended the standard clinical questions be used in the prior authorization review process.

Dr. Martin noted that should the Commissioner of Health approve this recommendation, DOH will proactively notify and educate the provider community about this decision.

A Committee member voiced concerns regarding the effect of this decision on community pharmacists.

After the Commissioner considered new financial information which became available subsequent to the Pharmacy and Therapeutics Committee meeting, the final determination for preferred and non-preferred drugs is as follows:

Preferred DrugsAranesp (darbepoetin alfa), Procrit (epoetin alfa)

Non-Preferred DrugsEpogen (epoetin alfa)

Proposal: Identification of preferred drugs in the category of Progestins (for Cachexia)

A. Based on the submitted or presented clinical information and on the financial information provided during the executive session, the Committee unanimously recommended the following:

B. The Committee unanimously recommended the standard clinical questions be used as the basis for approving use of a non-preferred drug, should the Commissioner's final decision include a non-preferred drug.

A. Based on the submitted or presented clinical information and on the financial information provided during the executive session, the Committee unanimously recommended the following:

Preferred Drugs
Alphagan P (brimonidine), brimonidine

Non-preferred DrugsIopidine (apraclonidine)

B. The Committee unanimously recommended the standard clinical questions be used in the prior authorization review process.

Approved as Recommended

G. Additional Discussion:

Dr. Martin expressed appreciation to the Committee, and on behalf of the Committee to State staff, First Health Services Corporation, and all others involved for making the Pharmacy and Therapeutics
Committee meetings possible.

The meeting adjourned at 2:50 PM.

Meeting Summary Posted 1/18/08

H. Final Determinations

The Commissioner has determined that the Medicaid program will require prior authorization under the Preferred Drug Program (PDP) for non-preferred drugs, as listed above, in the following classes:
Growth Hormones, Erythropoiesis Stimulating Agents, Progestins (for cachexia), Carbamazepine Derivatives, Ophthalmic Non-Steroidal Anti-Inflammatory Drugs, and Ophthalmic Alpha-2 Adrenergic Agonists (for
glaucoma).

Preferred Drugs will not require prior authorization

The impact of this final determination is as follows:

State Public Health Population:

Minimal effect on Medicaid enrollees, as a large majority of enrollees currently utilize preferred products.

Non-preferred products remain available when prior authorized.

Program Providers:

No impact on prescribers or pharmacies when utilizing preferred products. Prescribers, or their agents, will need to initiate the prior authorization process when ordering non-preferred products.
Pharmacies will need to complete the prior authorization process for non-preferred products.

State Health Program:

Annual gross savings associated with these therapeutic classes under the PDP are estimated at $13.6 M. The savings are achieved through changes in utilization to equally effective and less
expensive drugs through the receipt of supplemental rebates from pharmaceutical manufacturers.